Sulfinylpyridines and their use in the treatment of cancer

ABSTRACT

There is provided compounds of formula I (I) or pharmaceutically-acceptable salts thereof, wherein L, R 1 , R 2 , R 3 , R 4  and n have meanings provided in the description, which compounds are useful in the treatment of cancers.

FIELD OF THE INVENTION

The present invention relates to novel compounds and compositions, andtheir use in the treatment of cancer. In particular, the inventionrelates to novel compounds, compositions and methods for the treatmentof cancers through specific and potent inhibition of thioredoxinreductase with minimal inhibition of glutathione reductase.

BACKGROUND OF THE INVENTION

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Although the increased understanding of the role of oncogenes, and thedevelopment of new anticancer treatments and diagnosis, have improvedthe life expectancy of cancer patients, there is still a high medicalneed to find more effective and less toxic treatments for cancers, suchas breast cancer, glioblastoma, head and neck cancer, melanoma,leukaemia, and colon and lung cancer.

It is well known that excessive production of reactive oxygen species isa common feature of cancer cells due to their distorted metabolism andexaggerated replicative drive. Cancer cells are able to survive theirunnaturally high production of reactive oxygen species throughconcomitant up regulation of robust antioxidant defence mechanisms.

Radiotherapy and chemotherapy protocols compete against antioxidantdefence mechanisms, further increasing reactive oxygen species levelsbeyond adapted thresholds through targeting of multiple cellularcompartments and targets. Thus, sensitization of cancer cells to theirendogenous reactive oxygen species production can additionally inducecancer cell death. In contrast, normal cells have reserved capacity tocombat oxidative stress. With this in mind, it has been suggested thatif reactive oxygen species levels could be further increased, or thecellular defences against reactive oxygen species could be deliberatelyimpaired, these systems may serve to allow for a possible therapeuticmechanism of action for anticancer therapy (Luo, J., Solimini, N. L. &Elledge, S. J., Cell, 136, 823 (2009); Trachootham, D., Alexandre, J. &Huang, P., Nat Rev Drug Discov, 8, 579 (2009)).

Increased tolerance to oxidative stress of cancer cells can occurthrough activation of the two major antioxidant systems in human andother mammals: the glutathione and thioredoxin systems. Concomitantinhibition of the glutathione and thioredoxin systems therefore has beenproposed as a mechanism for anticancer activity (Harris, I. S., et al.,Cancer Cell 27, 211 (2015); Mandal, P. K., et al., Cancer Res, 70,9505-9514 (2010); Fath, M. A., Ahmad, I. M., Smith, C. J., Spence, J. &Spitz, D. R., Clin Cancer Res., 17, 6206 (2011)).

Cytosolic thioredoxin reductase is a key enzyme for the whole cytosolicthioredoxin system, which in turn is responsible for a cascade ofsignalling events and antioxidant activities (Amer, E. S. J., BiochimBiophys Acta, 1790, 495-526 (2009)). A high expression level ofcytosolic thioredoxin reductase in various cancers correlates to a moresevere cancer phenotype, chemotherapeutic drug resistance, and poorprognosis.

However, as normal, non-cancerous cells require either the glutathioneor the thioredoxin systems for survival (Amer, E. S. & Holmgren, A., EurJ Biochem, 267, 6102 (2000); Lillig, C. H., Berndt, C. & Holmgren, A.,Biochim Biophys Acta, 1780, 1304 (2008); Prigge, J. R., et al., FreeRadic Biol Med, 52, 803 (2012)), it is difficult to therapeuticallytarget both of these antioxidant systems without triggering majorunwanted toxicities.

It has been suggested that several chemotherapeutic protocols foranticancer treatment involve inhibition of cytosolic thioredoxinreductase together with other components of the cell (Becker, K. et al.Eur. J. Biochem., 267, 6118 (2000)). For example, motexafin gadolinium,marketed as a radiosensitizing drug and thioredoxin reductase inhibitor,is also a potent ribonucleotide reductase inhibitor (Hashemy, S. I.,Ungerstedt, J. S., Zahedi Avval, F. & Holmgren, A., J Biol Chem, 281,10691 (2006)). Auranofin, a potent thioredoxin reductase inhibitor,concomitantly localizes to and damages the mitochondria (Cox, A. G.,Brown, K. K., Arnér, E. S. & Hampton, M. B., Biochem Pharmacol, 76,1097-1109 (2008); Krishnamurthy, D., et al., J Med Chem, 51, 4790(2008); Rigobello, M. P., Folda, A., Baldoin, M. C., Scutari, G. &Bindoli, A., Free Radic Res, 39, 687 (2005)).

The structure and function of thioredoxin reductase, biological effectsassociated with its inhibition, such as in its potential as a mechanismfor cancer treatment, and compounds previously disclosed as potentialinhibitors are reviewed in Zhang, B. et al., Expert Opinion onTherapeutic Patents (2016).

The present innovation relates to the development and usage of novelcompounds specifically and potently targeting cytosolic thioredoxinreductase, without targeting the closely related flavoproteinglutathione reductase that supports the function of the glutathionesystem, as a means of obtaining a new efficient anticancer treatmentthat at the same time presents limited toxic side effects.

In particular, the inventors have unexpectedly found that novel,sulfinyl pyridine compounds may achieve highly selective inhibition ofcytosolic thioredoxin reductase by acting as strongly-binding (and, insome cases, effectively irreversible) inhibitors of the enzyme withoutcausing significant inhibition of glutathione reductase.

Specifically, by potently inhibiting thioredoxin reductase selectivelyover glutathione reductase, the novel sulfinyl pyridines have thepotential to be effective against cancer forms having dysfunctionalredox status, with minimal general toxic effects to normal cells. Suchinhibitors may also be a suitable adjuvant therapy to be used inconjunction with radiotherapies or other chemotherapeutic approaches.Based on these surprising results, the present invention aims to providenew treatments for cancers.

EP 0 337 560 describes antimicrobial (fungicidal) compounds foragricultural use. It provides no suggestion relating to the use of suchcompounds in medicine or as anticancer agents.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that certain nitro-substituted pyridines linkedvia a sulfinyl moiety to an optionally substituted phenyl group havesurprising properties which render such compounds useful in thetreatment of cancers.

Compounds of the Invention

In a first aspect of the invention, there is provided a compound offormula I

or a pharmaceutically acceptable salt thereof, wherein:L represents —S(O)—;n represents 0 to 5;R¹, R² and R³ each independently represent H, halo, R^(a1), —CN,-A^(a1)-C(Q^(a1))R^(b1), -A^(b1)-C(Q^(b1))N(R^(c1))R^(d1),-A^(c1)-C(Q^(c1))OR^(e1), -A^(d1)-S(O)_(p)R^(f1),-A^(e1)-S(O)_(p)N(R^(g1))R^(h1), -A^(f1)-S(O)_(p)OR^(i1), —N₃,—N(R^(j1))R^(k1), —N(H)CN, —NO₂, —ONO₂, —OR^(l1) or —SR^(m1);each A^(a1) to A^(f1) independently represents a single bond,—N(R^(p1))— or —O—;each Q^(a1) to Q^(c1) independently represents ═O, ═S, ═NR^(n1) or═N(OR^(o1));each R^(a1) and R^(f1) independently represents C₁₋₆ alkyl, C₂₋₆ alkenylor C₂₋₆ alkynyl each optionally substituted by one or more groupsindependently selected from G^(1a), heterocyclyl optionally substitutedby one or more groups independently selected from G^(1b), aryloptionally substituted by one or more groups independently selected fromG^(1c), or heteroaryl optionally substituted by one or more groupsindependently selected from G^(1d);each R^(b1), R^(c1), R^(d1), R^(e1), R^(g1), R^(h1), R^(i1), R^(j1),R^(k1), R^(l1), R^(m1), R^(n1), R^(o1) and R^(p1) independentlyrepresents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionallysubstituted by one or more groups independently selected from G^(1a),heterocyclyl optionally substituted by one or more groups independentlyselected from G^(1b), aryl optionally substituted by one or more groupsindependently selected from G^(1c), or heteroaryl optionally substitutedby one or more groups independently selected from G^(1d); or any ofR^(c1) and R^(d1), R^(g1) and R^(h1) and/or R^(j1) and R^(k1) are linkedtogether to form, together with the nitrogen atom to which they areattached, a 3- to 6-membered ring, which ring optionally contains onefurther heteroatom and which ring optionally is substituted by one ormore groups independently selected from halo, C₁₋₃ alkyl, C₂₋₃ alkenylor C₂₋₃ alkynyl each optionally substituted by one or more halo, and ═O;each R⁴ independently represents halo, R^(a2), —CN,-A^(a2)-C(Q^(a2))R^(b2), -A^(b2)-C(Q^(b2))N(R^(c2))R^(d2),-A^(c2)-C(Q^(c2))OR^(e2), -A^(d2)-S(O)_(q)R^(f2),-A^(e2)-S(O)_(q)N(R^(g2))R^(h2), -A^(f2)-S(O)_(q)OR^(i2), —N₃,—N(R^(j2))R^(k2), —N(H)CN, —NO₂, —ONO₂, —OR^(l2) or —SR^(m2);each Q^(a2) to Q^(c2) independently represents ═O, ═S, ═NR^(n2) or═N(OR^(o2));each A^(a2) to A^(f2) independently represents a single bond,—N(R^(p2))— or —O—;each R^(a2) and R^(f2) independently represents C₁₋₆ alkyl, C₂₋₆ alkenylor C₂₋₆ alkynyl each optionally substituted by one or more groupsindependently selected from G^(1a), heterocyclyl optionally substitutedby one or more groups independently selected from G^(2b), aryloptionally substituted by one or more groups independently selected fromG^(1c), or heteroaryl optionally substituted by one or more groupsindependently selected from G^(2d);each R^(b2), R^(c2), R^(d2), R^(e2), R^(g2), R^(h2), R^(i2), R^(j2),R^(k2), R^(l2), R^(m2), R^(n2), R^(o2) and R^(p2) independentlyrepresents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionallysubstituted by one or more groups independently selected from G^(1a),heterocyclyl optionally substituted by one or more groups independentlyselected from G^(2b), aryl optionally substituted by one or more groupsindependently selected from G^(2c), or heteroaryl optionally substitutedby one or more groups independently selected from G^(2d); orany two R^(c2) and R^(d2), R^(g2) and R^(h2) and/or R^(j2) and R^(k2)are linked together to form, along with the nitrogen atom to which theyare attached, a 3- to 6-membered ring, which ring optionally containsone further heteroatom and which ring optionally is substituted by oneor more groups independently selected from halogen, C₁₋₃ alkyl, C₂₋₃alkenyl or C₂₋₃ alkynyl each optionally substituted by one or morehalogens, and =0;each G^(1a), G^(1b), G^(1c), G^(1d), G^(2a), G^(2b), G^(1c) and G^(2d)independently represents halo, —CN, —N(R^(a3))R^(b3), —OR^(c3), —SR^(d3)or =0;each R^(a3), R^(b3), R^(c3) and R^(d3) independently represents H, orC₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted byone or more fluoro;or R^(a3) and R^(b3) are linked together to form, along with thenitrogen atom to which they are attached, a 3- to 6-membered ring, whichring optionally contains one further heteroatom and which ringoptionally is substituted by one or more groups independently selectedfrom fluoro, C₁₋₃ alkyl optionally substituted by one or more fluoro,and ═O; andeach p and q independently represents 1 or 2,which compounds and pharmaceutically acceptable salts thereof may bereferred to as compounds of the invention,but with the proviso that the compound of formula I does not represent:

-   3-nitro-2-(phenylsulfinyl)pyridine;-   3-nitro-2-(p-tolylsulfinyl)pyridine;-   2-((4-bromophenyl)sulfinyl)-3-nitropyridine;-   2-((3-chlorophenyl)sulfinyl)-3-nitropyridine; or-   3-nitro-2-((3-(trifluoromethyl)phenyl)-sulfinyl)pyridine.

For the avoidance of doubt, compounds of formula I and pharmaceuticallyacceptable salts thereof, not including the proviso, may be referred toherein as compounds of the invention. Similarly, compounds of the firstaspect of the invention will refer to compounds of formula I as definedin the first aspect of the invention, including the proviso, andpharmaceutically acceptable salts thereof. As such, compounds of thefirst aspect of the invention represent a particular embodiment ofcompounds of the invention.

The skilled person will understand that references herein to compoundsof the invention (e.g. compounds of the first aspect of the invention)will include references to all embodiments and particular forms thereof.

Unless indicated otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention pertains.

Pharmaceutically-acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compound ofthe invention with one or more equivalents of an appropriate acid orbase, optionally in a solvent, or in a medium in which the salt isinsoluble, followed by removal of said solvent, or said medium, usingstandard techniques (e.g. in vacuo, by freeze-drying or by filtration).Salts may also be prepared by exchanging a counter-ion of a compound ofthe invention in the form of a salt with another counter-ion, forexample using a suitable ion exchange resin.

Particular acid addition salts that may be mentioned include carboxylatesalts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate,heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate,propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate,α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate,phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate,o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate,oxalate, malonate, succinate, suberate, sebacate, fumarate, malate,maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts),halide salts (e.g. chloride, bromide or iodide salts), sulfonate salts(e.g. benzenesulfonate, methyl-, bromo- or chloro-benzenesulfonate,xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate,hydroxyethanesulfonate, 1- or 2-naphthalene-sulfonate or1,5-naphthalenedisulfonate salts) or sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, andthe like.

Particular base addition salts that may be mentioned include saltsformed with alkali metals (such as Na and K salts), alkaline earthmetals (such as Mg and Ca salts), organic bases (such as ethanolamine,diethanolamine, triethanolamine, tromethamine and lysine) and inorganicbases (such as ammonia and aluminium hydroxide). More particularly, baseaddition salts that may be mentioned include Mg, Ca and, mostparticularly, K and Na salts.

For the avoidance of doubt, compounds of the invention may exist assolids, and thus the scope of the invention includes all amorphous,crystalline and part crystalline forms thereof, and may also exist asoils. Where compounds of the invention exist in crystalline and partcrystalline forms, such forms may include solvates, which are includedin the scope of the invention. Compounds of the invention may also existin solution.

Compounds of the invention may contain double bonds and may thus existas E (entgegen) and Z (zusammen) geometric isomers about each individualdouble bond. All such isomers and mixtures thereof are included withinthe scope of the invention.

Compounds of the invention may also exhibit tautomerism. All tautomericforms and mixtures thereof are included within the scope of theinvention.

Compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation. Thevarious stereoisomers may be isolated by separation of a racemic orother mixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desired opticalisomers may be made by reaction of the appropriate optically activestarting materials under conditions which will not cause racemisation orepimerisation (i.e. a ‘chiral pool’ method), by reaction of theappropriate starting material with a ‘chiral auxiliary’ which cansubsequently be removed at a suitable stage, by derivatisation (i.e. aresolution, including a dynamic resolution); for example, with ahomochiral acid followed by separation of the diastereomeric derivativesby conventional means such as chromatography, or by reaction with anappropriate chiral reagent or chiral catalyst all under conditions knownto the skilled person. All stereoisomers and mixtures thereof areincluded within the scope of the invention.

Similarly, compounds of the invention may also contain one or moreasymmetric sulfur atoms (such as at the essential sulfinyl group) andmay therefore exhibit optical and/or diastereoisomerism as a resultthereof. Again, all stereoisomers and mixtures thereof are includedwithin the scope of the invention.

As used herein, references to halo and/or halogen will independentlyrefer to fluoro, chloro, bromo and iodo (for example, fluoro andchloro).

Unless otherwise specified, C_(1-z) alkyl groups (where z is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of two or three, as appropriate)of carbon atoms, be branched-chain, and/or cyclic (so forming a C_(3-z)cycloalkyl group). When there is a sufficient number (i.e. a minimum offour) of carbon atoms, such groups may also be part cyclic (so forming aC_(3-z) partial cycloalkyl group). Part cyclic alkyl groups that may bementioned include cyclopropylmethyl and cyclohexylethyl. When there is asufficient number of carbon atoms, such groups may also be multicyclic(e.g. bicyclic or tricyclic) or spirocyclic.

Unless otherwise specified, C_(2-z) alkenyl groups (where z is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of three) of carbon atoms, bebranched-chain, and/or cyclic (so forming a C_(4-z) cycloalkenyl group).When there is a sufficient number (i.e. a minimum of five) of carbonatoms, such groups may also be part cyclic. Part cyclic alkenyl groupsthat may be mentioned include cyclopentenylmethyl andcyclohexenylmethyl. When there is a sufficient number of carbon atoms,such groups may also be multicyclic (e.g. bicyclic or tricyclic) orspirocyclic.

Unless otherwise specified, C_(2-z) alkynyl groups (where z is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of four) of carbon atoms, bebranched-chain.

For the avoidance of doubt, the skilled person will understand that theterm alkyl will refer to saturated hydrocarbon moieties, whereas theterm alkenyl will refer to unsaturated hydrocarbon moieties containingat least one carbon-carbon double bond and the term alkynyl will referto unsaturated hydrocarbon moieties containing at least onecarbon-carbon triple bond, which alkyl, alkenyl and alkynyl groups maybe referred to collectively as hydrocarbyl groups. Further, suchunsaturated hydrocarbon moieties will be referred to by reference to thehighest degree of unsaturation comprised therein (e.g. a hydrocarbonmoiety comprising at least one carbon-carbon double bond and at leastone carbon-carbon triple bond will be referred to as alkynyl, althoughsuch moieties may also be referred to using terms such as “alkenylalkynyl” and the like).

As used herein, the term heterocyclyl may refer to non-aromaticmonocyclic and bicyclic heterocyclyl groups (which groups may further bebridged) in which at least one (e.g. one to four) of the atoms in thering system is other than carbon (i.e. a heteroatom), and in which thetotal number of atoms in the ring system is between three and twelve(e.g. between five and ten and, most preferably, between three andeight, e.g. a 5- or 6-membered heterocyclyl group). Further, suchheterocyclyl groups may be saturated, forming a heterocycloalkyl, orunsaturated containing one or more carbon-carbon or, where possible,carbon-heteroatom or heteroatom-heteroatom double and/or triple bonds,forming for example a C_(2-z) (e.g. C_(4-z)) heterocycloalkenyl (where zis the upper limit of the range) or a C_(7-z) heterocycloalkynyl group.C_(2-z) heterocyclyl groups that may be mentioned include7-azabicyclo-[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl,azetidinyl, 2,3-dihydroisothiazolyl, dihydropyranyl, dihydropyridyl,dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl),dithianyl (including 1,4-dithianyl), dithiolanyl (including1,3-dithiolanyl), imidazolidinyl, imidazolinyl, isothiazolidinyl,morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl,oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl,pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl,3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridyl(such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl),thietanyl, thiiranyl, thiolanyl, tetrahydrothiopyranyl, thiomorpholinyl,trithianyl (including 1,3,5-trithianyl), tropanyl and the like.Substituents on heterocyclyl groups may, where appropriate, be locatedon any atom in the ring system including a heteroatom. Further, in thecase where the substituent is another cyclic compound, then the cycliccompound may be attached through a single atom on the heterocyclylgroup, forming a so-called “spiro”-compound. The point of attachment ofheterocyclyl groups may be via any atom in the ring system including(where appropriate) a further heteroatom (such as a nitrogen atom), oran atom on any fused carbocyclic ring that may be present as part of thering system. Heterocyclyl groups may also be in the N- or S-oxidisedform.

At each occurrence when mentioned herein, particular heterocyclyl groupsthat may be mentioned include 3- to 8-membered heterocyclyl groups (e.g.a 4- to 6-membered heterocyclyl group).

As may be used herein, the term aryl includes references to C₆₋₁₄ (e.g.C₆₋₁₀) aromatic groups. Such groups may be monocyclic or bicyclic and,when bicyclic, be either wholly or partly aromatic. C₆₋₁₀ aryl groupsthat may be mentioned include phenyl, naphthyl,1,2,3,4-tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyland the like, such as phenyl). For the avoidance of doubt, the point ofattachment of substituents on aryl groups may be via any carbon atom ofthe ring system.

As may be used herein, the term heteroaryl (or heteroaromatic) includesreferences to 5- to 14- (e.g. 5- to 10-) membered heteroaromatic groupscontaining one or more heteroatoms selected from oxygen, nitrogen and/orsulfur. Such heteroaryl groups may comprise one, two, or three rings, ofwhich at least one is aromatic. Substituents onheteroaryl/heteroaromatic groups may, where appropriate, be located onany atom in the ring system including a heteroatom. The point ofattachment of heteroaryl/heteroaromatic groups may be via any atom inthe ring system including (where appropriate) a heteroatom. Bicyclicheteroaryl/heteroaromatic groups may comprise a benzene ring fused toone or more further aromatic or non-aromatic heterocyclic rings, inwhich instances, the point of attachment of the polycyclicheteroaryl/heteroaromatic group may be via any ring including thebenzene ring or the heteroaryl/heteroaromatic or heterocycloalkyl ring.Examples of heteroaryl/heteroaromatic groups that may be mentionedinclude pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl,thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl,imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl,azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl,quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl,benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl andpurinyl. The oxides of heteroaryl/heteroaromatic groups are alsoembraced within the scope of the invention (e.g. the N-oxide). As statedabove, heteroaryl includes polycyclic (e.g. bicyclic) groups in whichone ring is aromatic (and the other may or may not be aromatic). Hence,other heteroaryl groups that may be mentioned include e.g.benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazole,3,4-dihydrobenz[1,4]oxazinyl, dihydrobenzothiophenyl, indolinyl,5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl,thiochromanyl and the like.

For the avoidance of doubt, as used herein, references to heteroatomswill take their normal meaning as understood by one skilled in the art.Particular heteroatoms that may be mentioned include phosphorus,selenium, tellurium, silicon, boron, oxygen, nitrogen and sulfur (e.g.oxygen, nitrogen and sulfur).

For the avoidance of doubt, references to polycyclic (e.g. bicyclic)groups (e.g. when employed in the context of heterocycloalkyl groups)will refer to ring systems wherein more than two scissions would berequired to convert such rings into a straight chain, with the minimumnumber of such scissions corresponding to the number of rings defined(e.g. the term bicyclic may indicate that a minimum of two scissionswould be required to convert the rings into a straight chain). For theavoidance of doubt, the term bicyclic (e.g. when employed in the contextof heterocycloalkyl groups) may refer to groups in which the second ringof a two-ring system is formed between two adjacent atoms of the firstring, and may also refer to groups in which two non-adjacent atoms arelinked by either an alkylene or heteroalkylene chain (as appropriate),which later groups may be referred to as bridged.

For the avoidance of doubt, when an aryl or an heteroaryl group issubstituted with a group via a double bond, such as ═O, it is understoodthat the aryl or heteroaryl group is partly aromatic, i.e. the aryl orheteroaryl group consists of at least two rings where at least one ringis not aromatic.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature (or the most abundant one found in nature). Allisotopes of any particular atom or element as specified herein arecontemplated within the scope of the compounds of the invention. Hence,the compounds of the invention also include deuterated compounds, i.e.in which one or more hydrogen atoms are replaced by the hydrogen isotopedeuterium.

For the avoidance of doubt, in cases in which the identity of two ormore substituents in a compound of the invention may be the same, theactual identities of the respective substituents are not in any wayinterdependent. For example, in the situation in which two or more R⁴groups are present, those R⁴ groups may be the same or different.Similarly, where two or more R⁴ groups are present and each representR^(a2), the R^(2a) groups in question may be the same or different.Likewise, when more than one R^(a1) is present and each independentlyrepresents C₁₋₆ alkyl substituted by one or more G¹a group, theidentities of each G^(1a) are in no way interdependent.

For the avoidance of doubt, when a term such as “A^(a1) to A^(f1)” isemployed herein, this will be understood by the skilled person to meanA^(a1), A^(b1), A^(c1), A^(d1), A^(e1) and A^(f1) inclusively. Unlessotherwise stated, the same reasoning will apply to other such terms usedherein.

The skilled person will appreciate that compounds of the invention thatare the subject of this invention include those that are stable. Thatis, compounds of the invention include those that are sufficientlyrobust to survive isolation, e.g. from a reaction mixture, to a usefuldegree of purity.

All embodiments of the invention and particular features mentionedherein may be taken in isolation or in combination with any otherembodiments and/or particular features mentioned herein (hencedescribing more particular embodiments and particular features asdisclosed herein) without departing from the disclosure of theinvention.

For the avoidance of doubt, the compounds listed in the proviso providedin the first aspect of the invention (and therefore excluded ascompounds of formula I in the first aspect of the invention) may berepresented structurally as follows:

Particular compounds of the invention (including compounds of the firstaspect of the invention) that may be mentioned include those in which nrepresents 0 or 1. For example, particular compounds of the inventionthat may be mentioned include those in which n represents 1.

More particular compounds of the invention that may be mentioned includethose in which each R⁴ independently represents halo (such as chloro),—N(R^(j2))R^(k2), —ORl², or R^(a2).

Particular embodiments (i.e. of the first aspect of the invention) thatmay be mentioned include those in which:

each R^(a2) and R^(f2) independently represents C₁₋₆ alkyl, C₂₋₆ alkenylor C₂₋₆ alkynyl each optionally substituted by one or more groupsindependently selected from G^(1a), or heterocyclyl optionallysubstituted by one or more groups independently selected from G²b;each RP independently represents H, or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl each optionally substituted by one or more fluoro; andeach R^(b2), R^(c2), R^(d2), R^(e2), R^(g2), R^(h2), R^(k2), R^(j2),R^(k2), R^(l2), R^(m2), R^(n2) and R^(o2) independently represents H,C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted byone or more groups independently selected from G¹a, or heterocyclyloptionally substituted by one or more groups independently selected fromG^(2b); orany two R^(c2) and R^(d2), RP and R^(h2) and/or R^(j2) and R^(k2) arelinked together to form, along with the nitrogen atom to which they areattached, a 3- to 6-membered ring, which ring optionally contains onefurther heteroatom and which ring optionally is substituted by one ormore groups independently selected from halogen, C₁₋₃ alkyl, C₂₋₃alkenyl or C₂₋₃ alkynyl each optionally substituted by one or morehalogens, and ═O.

Yet more particular embodiments that may be mentioned include those inwhich each R⁴ independently represents halo, such as chloro.

Particular compounds of the invention that may be mentioned includethose in which:

n represents 0 or 1;each R⁴ (i.e. where present) independently represents halo (such aschloro), —N(R^(j2))R^(k2), —OR^(l2), or R^(a2);each R^(a2) independently represents C₁₋₆ alkyl (e.g. methyl) optionallysubstituted by one or more fluoro;andeach R^(j2), R^(k2) and R^(l2) independently represents H or C₁₋₆ alkyloptionally substituted by one or more fluoro.

More particular compounds of the invention that may be mentioned includethose in which:

n represents 1 or 0; andR⁴ represents halo (e.g. chloro) or C₁₋₆ alkyl optionally substituted byone or more fluoro (e.g. —CH₃).

Yet more particular compounds of the invention that may be mentionedinclude those in which:

n represents 1 or 0; andR⁴ represents halo (e.g. chloro) —OC₁₋₆ alkyl optionally substituted byone or more fluoro (e.g. —OCH₃) or C₁₋₆ alkyl optionally substituted byone or more fluoro (e.g. —CH₃).

For example, particular compounds of the invention that may be mentionedinclude those in which:

n represents 1; andR⁴ represents halo (e.g. chloro) or C₁₋₆ alkyl optionally substituted byone or more fluoro (e.g. —CH₃).

For example, particular compounds of formula I that may be mentionedinclude those in which:

n represents 1; andR⁴ represents halo (particularly, chloro).

Particular compounds of the invention that may be mentioned includethose in which n represents 1 to 5 and one of the R⁴ groups present isin the 4-position (i.e. the para position relative to the Lsubstituent). The skilled person will understand that, in such cases,compounds of the invention may be depicted as having one R⁴ in the4-position, with the remaining R⁴ groups depicted as (R⁴)_(n) with nthen representing 0 to 4 (or, alternatively, represented as(R^(4x))_(nx) with nx representing 0 to 4).

More particular compounds of the invention that may be mentioned includethose in which n represents 1 and the R⁴ group is present in the4-position (i.e. the para position relative to the L substituent).

Yet more particular compounds of the invention that may be mentionedinclude those in which n represents 1 and the R⁴ group is present in the4-position (i.e. the para position relative to the L substituent),wherein the R⁴ group represents halo (such as chloro).

In a particular embodiment, the compound of formula I is a compound offormula Ia

wherein:L, R¹, R² and R³ and are defined for compounds of formula I (i.e. asdefined for compounds of the invention, including all particularfeatures and embodiments thereof); andeach of R⁵ to R⁸ independently represents H or an R⁴ group as definedfor compounds of formula I (i.e. as defined for compounds of theinvention, including all particular features and embodiments thereof).

For the avoidance of doubt, where the compound of formula I is acompound of formula Ia, compounds of the invention includepharmaceutically acceptable salts of compounds of formula Ia.

In a particular embodiment (i.e. an embodiment of compounds of formulaIa), each of R⁵, R⁶, R⁸ and R⁹ represents H and R⁷ represents H or R⁴ asdefined for compounds of the invention (i.e. for compounds of formula Ias defined in the first aspect of the invention, including allparticular features and embodiments thereof).

In a yet more particular embodiment, each of R⁵, R⁶, R⁸ and R⁹represents H and R⁷ represents H or R⁴, wherein R⁴ represents halo (e.g.chloro).

Particular compounds of the invention (including compounds of formula Iand Ia) that may be mentioned include those in which each R¹, R² and R³each independently represents H, halo, R^(a1), —N(R^(j1))R^(k1) or—OR^(l1).

Particular embodiments (i.e. of the first aspect of the invention) thatmay be mentioned include those in which:

each R^(a1) and R^(f1) independently represents C₁₋₆ alkyl, C₂₋₆ alkenylor C₂₋₆ alkynyl each optionally substituted by one or more groupsindependently selected from G^(1a), or heterocyclyl optionallysubstituted by one or more groups independently selected from G^(1b);each R^(p1) independently represents H, or C₁₋₆ alkyl, C₂₋₆ alkenyl orC₂₋₆ alkynyl each optionally substituted by one or more fluoro; and

each R^(b1), R^(c1), R^(d1), R^(e1), R^(g1), R^(h1), R^(i1), R^(j1),R^(k1), R^(l1), R^(m1), R^(n1) and R^(o1) independently represents H,C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted byone or more groups independently selected from G^(1a), or heterocyclyloptionally substituted by one or more groups independently selected fromG^(1b); or

any of R^(c1) and R^(d1), R^(g1) and R^(h1) and/or R^(j1) and R^(k1) arelinked together to form, together with the nitrogen atom to which theyare attached, a 3- to 6-membered ring, which ring optionally containsone further heteroatom and which ring optionally is substituted by oneor more groups independently selected from halo, C₁₋₃ alkyl, C₂₋₃alkenyl or C₂₋₃ alkynyl each optionally substituted by one or more halo,and ═O.

More particular embodiments that may be mentioned include those inwhich:

each R¹, R² and R³ each independently represent H, halo, R^(a1),—N(R^(j1))R^(k1), —OR^(l1) or —SR^(m1) (e.g. H, halo, R^(a1),—N(R^(j1))R^(k1) or —OR^(l1); andeach R^(a1), R^(j1), R^(k1), R^(l1) and R^(m1) independently representC₁₋₆ alkyl (e.g. methyl) optionally substituted by one or more fluoro.

In particular embodiments that may be mentioned, only R^(c1) and R^(d1),and/or R^(g1) and R^(h1) may alternatively be linked together in themanner described herein.

In more particular embodiments that may be mentioned, G¹a groups wherepresent as a substituent on R^(1a) may not represent:

-   (i) —NR^(a3)(R^(b3)), particularly where R^(a3) and R^(b3) are    linked in the manner described herein; or-   (ii) —OR^(c3), particularly where R^(c3) represents a cycloalkyl    group.

In more particular embodiments that may be mentioned, G¹a groups wherepresent as a substituent on R^(1a) (which in such instances may bealternatively referred to as G^(1ax) groups) may represent halo, —CN,—SR^(d3) or ═O.

For example, compounds of the invention that may be mentioned includethose in which:

each R¹, R² and R³ each independently represent H or —OW; and/or (e.g.and)each R^(l1) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl (e.g. C₁₋₆ alkyl, such as C₁₋₃ alkyl) optionally substituted byone or more fluoro (such as methyl, difluoromethyl, trifluoromethyl).

In addition, compounds of the invention that may be mentioned includethose in which:

each R¹, R² and R³ each independently represent H, halo (e.g. chloro),—N(R^(j1))R^(k1) or

In particular, compounds of the invention that may be mentioned includethose in which:

each R¹, R² and R³ each independently represent H, halo (e.g. chloro),—N(R^(j1))R^(k1) or —OR^(l1);each R^(l1) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl (e.g. C₁₋₆ alkyl, such as C₁₋₃ alkyl) optionally substituted byone or more fluoro (such as methyl, difluoromethyl, trifluoromethyl);and each R^(j1) and R^(k1) independently represent C₁₋₆ alkyl, C₂₋₆alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl, such as C₁₋₃ alkyl) optionallysubstituted by one or more fluoro (such as methyl).

Yet more particular compounds of the invention that may be mentionedinclude those in which:

each R¹, R² and R³ each independently represent H or —OR^(l1); andeach R^(l1) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl (e.g. C₁₋₆ alkyl, such as C₁₋₃ alkyl) optionally substituted byone or more fluoro (such as methyl).

Particular compounds of the invention that may be mentioned includethose in which:

each of R¹, R² and R³ represent H; orat least one (e.g. one) of R¹, R² and R³ (e.g. R¹) represents a groupother than H (e.g. —OR^(l1), such as —OR^(l1) where R^(l1) representsC₁₋₆ alkyl (e.g. C₁₋₃ alkyl, such as methyl) optionally substituted byone or more fluoro) and the remainder of R¹, R² and R³ represent H.

For example, compounds of the invention that may be mentioned includethose in which:

each of R¹, R² and R³ represent H; orat least one (e.g. one) of R¹, R² and R³ (e.g. R¹) represents —OC₁₋₆alkyl optionally substituted by one or more fluoro (e.g. —OCH₃) and theremainder of R¹, R² and R³ represent H.

Thus, in a particular embodiment, there is provided a compound of theinvention (e.g. a compound of formula I or Ia) where:

R² and R³ represent H; and/orR¹ represents H, halo, R^(a1), —N(R^(j1))R^(k1), —OR^(l1) or —SR^(m1)(e.g. H, halo, R^(a1), —N(R_(j1))R^(k1) or —OR^(l1).

In a more particular embodiment, there is provided a compound of theinvention:

R² and R³ represent H; and/orR¹ represents H, halo, R^(a1), —N(R^(j1))R^(k1), —OR^(l1) or —SR^(m1)(e.g. H, halo, R^(a1), —N(R^(j1))R^(k1) or —OR^(l1)), andeach R^(a1), R^(j1), R^(k1), R^(l1) and R_(m1) independently representC₁₋₆ alkyl (e.g. C₁₋₃ alkyl, such as methyl) optionally substituted byone or more fluoro.

In a yet more particular embodiment, there is provided a compound of theinvention where: R² and R³ represent H; and/or

R¹ represents H or —OC₁₋₆ alkyl optionally substituted by one or morefluoro (e.g. —OCH₃).

In a further embodiment, there is provided a compound of the inventionwhere:

R² and R³ represent H; and/orR¹ represents H, halo (e.g. chloro), —NC₁₋₆ alkyl(C₁₋₆ alkyl) optionallysubstituted by one or more fluoro (e.g. —NCH₃(CH₃)), or —OC₁₋₆ alkyloptionally substituted by one or more fluoro (e.g. —OCH₃).

In particular embodiments, there are provided compounds of the inventionwherein R¹ represents —OC₁ alkyl optionally substituted by one or morefluoro (such as —OCH₃).

Thus, in a particular embodiment, there is provided a compound of theinvention where: R² and R³ represent H; and/or

R¹ represents —OC₁ alkyl optionally substituted by one or more fluoro(such as —OCH₃).

As indicated herein above, particular features and embodiments asdescribed herein may be combined without departing from the teaching ofthe invention.

For example, in a particular embodiment of the invention, there isprovided a compound of the invention wherein:

each R⁴ independently represents halo (such as chloro),—N(R^(j2))R^(k2), —OR^(l2), or R^(a2); andeach R¹, R² and R³ each independently represents H, halo, R^(a1),—N(R^(j1))R^(k1), —OR^(l1) or —SR^(m1);

Similarly, in a particular embodiment of the invention, there isprovided a compound of the invention wherein:

n represents 1 or 0;R⁴ represents halo (e.g. chloro);each R¹, R² and R³ each independently represent H or —OW; andeach R^(l1) independently represents C₁₋₆ alkyl (e.g. C₁₋₃ alkyl, suchas methyl) optionally substituted by one or more fluoro.

Particular compounds of the invention (including compounds of formula Iand Ia, and all embodiments and particular forms thereof) that may bementioned include the compounds of the examples as provided herein, or apharmaceutically acceptable salt thereof.

Where an example compound is indicated to have been obtained in aparticular salt form, the skilled person will understand that particularcompounds of the invention that may be mentioned include the free baseor free acid (as appropriate) of that compound, and vice versa. Further,where an example compound is indicated to have been obtained in aparticular salt form, particular compounds of the invention that may bementioned include other (i.e. different) pharmaceutically acceptablesalts of that compound.

Thus, for the avoidance of doubt, particular compounds of the inventionthat may be mentioned include:

-   2-((4-chlorophenyl)sulfinyl)-6-methoxy-3-nitropyridine,    and pharmaceutically acceptable salts thereof.

Compositions and Medical Uses

As discussed hereinbefore, compounds of the invention, and thereforecompositions and kits comprising the same, are useful aspharmaceuticals.

According to a second aspect of the invention there is provided acompound of the invention, as hereinbefore defined (i.e. in the firstaspect of the invention, including all embodiments and particularfeatures therein, but without the proviso), for use as a pharmaceutical.Further, there is provided a compound of the invention, as hereinbeforedefined, for use in medicine.

In a particular embodiment of the second aspect of the invention, thecompound of the invention is a compound of the first aspect of theinvention (i.e. including the proviso).

As indicated herein, compounds of the invention may be of particular usein treating cancers.

Thus, in a third aspect of the invention, there is provided a compoundof the invention, as hereinbefore defined (i.e. in the first aspect ofthe invention, including all embodiments and particular featurestherein, but without the proviso), for use in the treatment of cancer.

In an alternative third aspect of the invention, there is provided theuse of a compound of the invention, as hereinbefore defined, in themanufacture of a medicament for the treatment of cancer.

In a further alternative third aspect of the invention, there isprovided a method of treating cancer comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof the invention.

In a particular embodiment of the third aspect of the invention, thecompound of the invention is a compound of the first aspect of theinvention (i.e. including the proviso).

The skilled person will understand that references to the treatment of aparticular condition (or, similarly, to treating that condition) taketheir normal meanings in the field of medicine. In particular, the termsmay refer to achieving a reduction in the severity of one or moreclinical symptom associated with the condition. For example, in the caseof a cancer, the term may refer to achieving a reduction of the amountof cancerous cells present (e.g. in the case of a cancer forming a solidtumour, indicated by a reduction in tumour volume).

As used herein, references to patients will refer to a living subjectbeing treated, including mammalian (e.g. human) patients.

As used herein, the term effective amount will refer to an amount of acompound that confers a therapeutic effect on the treated patient. Theeffect may be objective (i.e.

measurable by some test or marker) or subjective (i.e. the subject givesan indication of and/or feels an effect).

Although compounds of the invention may possess pharmacological activityas such, certain pharmaceutically-acceptable (e.g. “protected”)derivatives of compounds of the invention may exist or be prepared whichmay not possess such activity, but may be administered parenterally ororally and thereafter be metabolised in the body to form compounds ofthe invention. Such compounds (which may possess some pharmacologicalactivity, provided that such activity is appreciably lower than that ofthe active compounds to which they are metabolised) may therefore bedescribed as “prodrugs” of compounds of the invention.

As used herein, references to prodrugs will include compounds that forma compound of the invention, in an experimentally-detectable amount,within a predetermined time, following enteral or parenteraladministration (e.g. oral or parenteral administration). All prodrugs ofthe compounds of the invention are included within the scope of theinvention.

Furthermore, certain compounds of the invention may possess no orminimal pharmacological activity as such, but may be administeredparenterally or orally, and thereafter be metabolised in the body toform compounds of the invention that possess pharmacological activity assuch. Such compounds (which also includes compounds that may possesssome pharmacological activity, but that activity is appreciably lowerthan that of the active compounds of the invention to which they aremetabolised), may also be described as “prodrugs”.

Thus, the compounds of the invention are useful because they possesspharmacological activity, and/or are metabolised in the body followingoral or parenteral administration to form compounds that possesspharmacological activity.

As indicated herein, the compounds of the invention may be useful in thetreatment of cancer (i.e. particular cancers).

Particular cancers that may be mentioned include those selected from thegroup comprising:

soft tissue cancers, such as sarcoma (e.g. angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma;lung cancers, such as bronchogenic carcinoma (e.g. squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (or bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, includingnon-small cell lung cancer;gastrointestinal cancers: such as esophageal cancers (e.g. squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach cancers(e.g. carcinoma, lymphoma, leiomyosarcoma), pancreatic cancers (e.g.ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel cancers (e.g. adenocarcinoma, lymphoma,carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,neurofibroma, fibroma), large bowel cancers (e.g. adenocarcinoma,tubular adenoma, villous adenoma, hamartoma, leiomyoma);genitourinary tract cancers, such as cancer of the kidney (e.g.adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia),bladder and urethra (e.g. squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (e.g. adenocarcinoma, sarcoma),testis (e.g. seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma);liver cancers, such as hepatoma (e.g. hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, hemangioma;bone cancers, such as osteogenic sarcoma (e.g. osteosarcoma),fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'ssarcoma, malignant lymphoma (e.g. reticulum cell sarcoma), multiplemyeloma, malignant giant cell tumor chordoma, osteochronfroma (e.gosteocartilaginous exostoses), benign chondroma, chondroblastoma,chondromyxofibroma, osteoid osteoma and giant cell tumors; cancers ofthe head and/or nervous system, such as cancer of the skull (e.g.osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(e.g. meningioma, meningiosarcoma, gliomatosis), brain (e.g.astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma),glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), spinal cord (e.g. neurofibroma, meningioma, glioma,sarcoma);gynecological cancers, such as cancers of the uterus (e.g. endometrialcarcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia),ovaries (e.g. ovarian carcinoma (serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma), granulosa-thecal celltumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma),cancers of the vulva (e.g. squamous cell carcinoma, intraepithelialcarcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (e.g. clearcell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonalrhabdomyosarcoma)), fallopian tubes (e.g. carcinoma);haematologic cancers, such as cancers of the blood and bone marrow (e.g.myeloid leukemia (acute and chronic), acute lymphoblastic leukemia,chronic lymphocytic leukemia, myeloproliferative diseases, multiplemyeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin'slymphoma (malignant lymphoma);skin cancers, such as malignant melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma,angioma, dermatofibroma, keloids; neurofibromatosis and Adrenal glands;andneuroblastomas.

As used herein, references to cancerous cells and the like will includereferences to a cell afflicted by any one of the above identifiedconditions.

More particular cancers that may be mentioned include thosecorresponding to the cell lines used in the examples provided herein.

For example, particular cancers that may be mentioned include breastcancer (such as mammary adenocarcinoma, e.g. metastatic mammaryadenocarcinoma) and/or glioblastoma (such as glioblastoma multiform).

More particular cancers that may be mentioned include:

head and neck cancer (such as throat cancer, e.g. pharyngeal squamouscell carcinoma);colon cancer (such as colorectal carcinoma);skin cancer (such as epidermoid (skin) carcinoma);gastrointestinal cancers (such as pancreatic cancer, e.g. pancreaticductal carcinoma);breast cancer (such as mammary adenocarcinoma, e.g. metastatic mammaryadenocarcinoma);lung cancer (such as carcinoma); andhaematologic cancers (such as leukemia, e.g. acute monocytic leukemia).

In particular embodiments, the cancer is a solid tumor cancer.

In more particular embodiments, the cancer is selected from pancreaticcancer, ovarian cancer and colorectal cancer.

For example, in certain embodiments, the cancer is selected fromcolorectal cancer (including those processing Ras mutations), small celllung cancer, non-small cell lung cancer (NSCLC), and glioma.

In other embodiments, the cancer is selected from non-small cell lungcancer, ovarian cancer, metastatic breast cancer, pancreatic cancer,hepatobiliary cancer (including hepatocellular cancer, bile duct cancerand cholangiocarcinoma), and gastric cancer.

In further embodiments, the cancer is selected from colorectal cancer(including Ras mutations), small cell lung cancer, non-small cell lungcancer, ovarian cancer, hepatobiliary cancer (including hepatocellularcancer, bile duct cancer and cholangiocarcinoma), gastric cancer,testicular cancer, and head and neck squamous cell carcinoma.

In certain embodiments of the present invention, the cancer is selectedfrom leukemia (including acute myeloid leukemia, acute lymphoblasticleukemia, chronic myeloid leukemia, and chronic lymphoid leukemia),lymphoma (including mantle cell lymphoma, Hodgkin's lymphoma andnon-Hodgkin's lymphoma), and prostate cancer

The skilled person will understand that treatment with compounds of theinvention may further comprise (i.e. be combined with) furthertreatment(s) for the same condition. In particular, treatment withcompounds of the invention may be combined with means for the treatmentof cancer, such as treatment with one or more other therapeutic agentthat is useful in the in the treatment of cancer and/or one or morephysical method used in the treatment of cancer (such as treatmentthrough surgery), as known to those skilled in the art.

In particular, treatment with compounds of the invention may beperformed in patients who are being or have been (i.e. as part or of atreatment for the same condition, such as within a month of treatmentwith compounds of the invention, such as within two weeks, e.g. within aweek or, particularly, on the same day) treated with a therapeutic agentor physical method that is capable of causing (e.g. can be demonstratedto cause) an increase in reactive oxygen species.

For the avoidance of doubt, the skilled person will understand thattherapeutic agents or physical methods capable of causing (e.g. can bedemonstrated to cause) an increase in reactive oxygen species may notnecessarily be effective treatments per se, but will become effectivewhen used in combination with compounds of the invention.

For the avoidance of doubt, the skilled person will understand thatcompounds of the invention may also be used in combination with one ormore other therapeutic agent that is useful in the in the treatment ofcancer and/or one or more physical method used in the treatment ofcancer (such as treatment through surgery) wherein such methods do notcause an increase in reactive oxygen species.

In particular, treatment with compounds of the invention may beperformed in patients who are being or have been treated withradiotherapy.

Thus, there is also provided:

a method of treating cancer in a patient in need thereof wherein thepatient is administered a therapeutically effective amount of a compoundof the invention in combination with treatment by radiotherapy (i.e.concomitantly or sequentially); anda compound of the invention for use in treating cancer in a patient whois also being treated with radiotherapy.

Compounds of the invention will normally be administered orally,intravenously, subcutaneously, buccally, rectally, dermally, nasally,tracheally, bronchially, sublingually, intranasally, topically, by anyother parenteral route or via inhalation, in a pharmaceuticallyacceptable dosage form.

Compounds of the invention may be administered alone or may beadministered by way of known pharmaceutical compositions/formulations,including tablets, capsules or elixirs for oral administration,suppositories for rectal administration, sterile solutions orsuspensions for parenteral or intramuscular administration, and thelike.

According to a fourth aspect of the invention there is thus provided apharmaceutical composition/formulation comprising a compound of theinvention as hereinbefore defined (i.e. in the first aspect of theinvention, including all embodiments and particular features therein,but without the proviso), and optionally (e.g. in admixture with) one ormore pharmaceutically acceptable adjuvant, diluent and/or carrier.

In a particular embodiment of the fourth aspect of the invention, thecompound of the invention is a compound of the first aspect of theinvention (i.e. including the proviso).

The skilled person will understand that references herein to compoundsof the invention being for particular uses (and, similarly, to uses andmethods of use relating to compounds of the invention) may also apply topharmaceutical compositions comprising compounds of the invention asdescribed herein.

Compounds of the invention may be administered in the form of tablets orcapsules, e.g. time-release capsules that are taken orally.Alternatively, the compounds of the invention may be in a liquid formand may be taken orally or by injection. The compounds of the inventionmay also be in the form of suppositories, or, creams, gels, and foamse.g. that can be applied to the skin. In addition, they may be in theform of an inhalant that is applied nasally or via the lungs.

The skilled person will understand that compounds of the invention mayact systemically and/or locally (i.e. at a particular site).

Compounds of the invention may be administered orally, intravenously,subcutaneously, buccally, rectally, dermally, nasally, tracheally,bronchially, by any other parenteral route or via inhalation, in apharmaceutically acceptable dosage form. Alternatively, particularlywhere compounds of the invention are intended to act locally, compoundsof the invention may be administered topically.

Thus, in a particular embodiment, the pharmaceutical formulation isprovided in a pharmaceutically acceptable dosage form, including tabletsor capsules, liquid forms to be taken orally or by injection,suppositories, creams, gels, foams, or inhalants (e.g. to be appliedintranasally). For the avoidance of doubt, in such embodiments,compounds of the invention may be present as a solid (e.g. a soliddispersion), liquid (e.g. in solution) or in other forms, such as in theform of micelles.

In more particular embodiments, the pharmaceutical formulation isprovided the form of a tablets or capsules, liquid forms to be takenorally or by injection (e.g. a form suitable for intravenous injection).In particular, injection may take place using conventional means, andmay include the use of microneedles.

Depending on e.g. potency and physical characteristics of the compoundof the invention (i.e. active ingredient), pharmaceutical formulationsthat may be mentioned include those in which the active ingredient ispresent in at least 1% (or at least 10%, at least 30% or at least 50%)by weight. That is, the ratio of active ingredient to the othercomponents (i.e. the addition of adjuvant, diluent and carrier) of thepharmaceutical composition is at least 1:99 (or at least 10:90, at least30:70 or at least 50:50) by weight.

As described herein, compounds of the invention may also be combinedwith one or more other (i.e. different, e.g. agents other than compoundsof formula I) therapeutic agents that are useful in the treatment ofcancer. Such combination products that provide for the administration ofa compound of the invention in conjunction with one or more othertherapeutic agent may be presented either as separate formulations,wherein at least one of those formulations comprises a compound of theinvention, and at least one comprises the other therapeutic agent, ormay be presented (i.e. formulated) as a combined preparation (i.e.presented as a single formulation including a compound of the inventionand the one or more other therapeutic agent).

Thus, according to a fifth aspect of the invention, there is provided acombination product comprising:

(A) a compound of the invention as hereinbefore defined (i.e. in thefirst aspect of the invention, including all embodiments and particularfeatures therein, but without the proviso); and(B) one or more other therapeutic agent that is useful in the treatmentof cancer, wherein each of components (A) and (B) is formulated inadmixture, optionally with one or more a pharmaceutically-acceptableadjuvant, diluent or carrier.

In a sixth aspect of the invention there is provided a kit-of-partscomprising:

(a) a pharmaceutical formulation as hereinbefore defined (i.e. in thefourth aspect of the invention); and(b) one or more other therapeutic agent that is useful in the treatmentof cancer, optionally in admixture with one or morepharmaceutically-acceptable adjuvant, diluent or carrier,which components (a) and (b) are each provided in a form that issuitable for administration in conjunction (i.e. concomitantly orsequentially) with the other.

In particular embodiments of the fourth and fifth aspects of theinvention, the compound of the invention is a compound of the firstaspect of the invention (i.e. including the proviso).

The skilled person will understand that compounds of the invention, andpharmaceutically-acceptable salts thereof, may be administered (forexample, as formulations as described hereinabove) at varying doses,with suitable doses being readily determined by one of skill in the art.Oral, pulmonary and topical dosages (and subcutaneous dosages, althoughthese dosages may be relatively lower) may range from between about 0.01μg/kg of body weight per day (μg/kg/day) to about 200 μg/kg/day,preferably about 0.01 to about 10 μg/kg/day, and more preferably about0.1 to about 5.0 μg/kg/day. For example, when administered orally,treatment with such compounds may comprise administration of aformulations typically containing between about 0.01 μg to about 2000mg, for example between about 0.1 μg to about 500 mg, or between 1 μg toabout 100 mg (e.g. about 20 μg to about 80 mg), of the activeingredient(s). When administered intravenously, the most preferred doseswill range from about 0.001 to about 10 μg/kg/hour during constant rateinfusion. Advantageously, treatment may comprise administration of suchcompounds and compositions in a single daily dose, or the total dailydosage may be administered in divided doses of two, three or four timesdaily (e.g. twice daily with reference to the doses described herein,such as a dose of 10 mg, 20 mg, 30 mg or 40 mg twice daily).

In any event, the physician, or the skilled person, will be able todetermine the actual dosage which will be most suitable for anindividual patient, which is likely to vary with the route ofadministration, the type and severity of the condition that is to betreated, as well as the species, age, weight, sex, renal function,hepatic function and response of the particular patient to be treated.The above-mentioned dosages are exemplary of the average case; therecan, of course, be individual instances where higher or lower dosageranges are merited, and such are within the scope of this invention.

Preparation of Compounds/Compositions

Pharmaceutical compositions/formulations, combination products and kitsas described herein may be prepared in accordance with standard and/oraccepted pharmaceutical practice.

Thus, in a further aspect of the invention there is provided a processfor the preparation of a pharmaceutical composition/formulation, ashereinbefore defined, which process comprises bringing into associationa compound of the invention, as hereinbefore defined, with one or morepharmaceutically-acceptable adjuvant, diluent or carrier.

In further aspects of the invention, there is provided a process for thepreparation of a combination product or kit-of-parts as hereinbeforedefined, which process comprises bringing into association a compound ofthe invention, as hereinbefore defined, or a pharmaceutically acceptablesalt thereof with the other therapeutic agent that is useful in thetreatment of cancer, and at least one pharmaceutically-acceptableadjuvant, diluent or carrier.

As used herein, references to bringing into association will mean thatthe two components are rendered suitable for administration inconjunction with each other.

Thus, in relation to the process for the preparation of a kit of partsas hereinbefore defined, by bringing the two components “intoassociation with” each other, we include that the two components of thekit of parts may be:

(i) provided as separate formulations (i.e. independently of oneanother), which are subsequently brought together for use in conjunctionwith each other in combination therapy; or(ii) packaged and presented together as separate components of a“combination pack” for use in conjunction with each other in combinationtherapy.

Compounds of the invention as described herein may be prepared inaccordance with techniques that are well known to those skilled in theart, such as those described in the examples provided hereinafter.

According to a seventh aspect of the invention there is provided aprocess for the preparation of a compound of the first aspect of theinvention as hereinbefore defined (i.e. a compound of the invention butincluding the proviso), which process comprises:

(i) reaction of a compound of formula II

wherein R¹ to R⁴ and n are as defined herein in formula I (or anyparticular feature or embodiments thereof), with a suitable oxidisingagent (such as meta-chloroperoxybenzoic acid (mCPBA)) in the presence ofa suitable solvent (such as dichloromethane (DCM)), under conditionsknown to those skilled in the art.

Compounds of formulae II may be obtained either by analogy with theprocesses described herein, or by conventional synthetic procedures, inaccordance with standard techniques, from available starting materialsusing appropriate reagents and reaction conditions. In this respect, theskilled person may refer to inter alia “Comprehensive Organic Synthesis”by B. M. Trost and I. Fleming, Pergamon Press, 1991. Further referencesthat may be employed include “Heterocyclic Chemistry” by J. A. Joule, K.Mills and G. F. Smith, 3^(rd) edition, published by Chapman & Hall,“Comprehensive Heterocyclic Chemistry II” by A. R. Katritzky, C. W. Reesand E. F. V. Scriven, Pergamon Press, 1996 and “Science of Synthesis”,Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag,2006.

In particular, compounds of formula II may be prepared by reaction of acompound of formula III

wherein R⁴ and n are as defined herein in formula I (or any particularfeature or embodiments thereof), with a compound of formula IV

wherein R¹, R² and R³ are as defined herein in formula I (or anyparticular feature or embodiment thereof) and LG¹ represents a suitableleaving group (such as halo, e.g. chloro), under conditions known tothose skilled in the art, such as in the presence of a suitable base(such as a metal carbonate, e.g. potassium carbonate, a metal hydroxide,e.g. sodium hydroxide, or an amine base, e.g. triethyl amine), and inthe presence of a suitable solvent (such as a polar organic solvent,e.g. N,N′-dimethylacetamide, N,N′-dimethylformamide or tetrahydrofuran,or a mixture of a polar organic solvent and water), under conditionsknown to those skilled in the art.

Compounds of formulae III and IV are either commercially available, areknown in the literature, or may be obtained either by analogy with theprocesses described herein, or by conventional synthetic procedures, inaccordance with standard techniques, from available starting materialsusing appropriate reagents and reaction conditions.

The substituents R¹ to R⁴ (or, when the compound of formula I is acompound of formula Ia, the substituents R¹ to R³ and R⁵ to R⁹), ashereinbefore defined, may be modified one or more times, after or duringthe processes described above for preparation of compounds of formula I(including compounds of formula Ia) by way of methods that are wellknown to those skilled in the art. Examples of such methods includesubstitutions, reductions, oxidations, dehydrogenations, alkylations,dealkylations, acylations, hydrolyses, esterifications, etherifications,halogenations and nitrations. The precursor groups can be changed to adifferent such group, or to the groups defined in formula I, at any timeduring the reaction sequence. The skilled person may also refer to“Comprehensive Organic Functional Group Transformations” by A. R.Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995 and/or“Comprehensive Organic Transformations” by R. C. Larock, Wiley-VCH,1999.

In a further aspect of the invention, there is provided a compound offormula IV as defined herein (i.e. wherein R¹, R², R³, R⁴ and n are asdefined herein, including all particular features and embodimentsthereof), or a pharmaceutically acceptable salt thereof.

In a particular embodiment, there is provided compounds of formula IVwherein:

R¹ represents halo, —N(R^(i1))R^(k1), or —SR^(m1) (such as halo,—N(R^(j1))R^(k1), —OR^(l1) or —SR^(m1), e,g. —OR^(l1)) and/or (e.g. and)R² and R³ represent H.

Particular compounds of formula IV that may be mentioned include thoseprepared in the examples provided herein, and pharmaceuticallyacceptable salts thereof.

Compounds of the invention may be isolated from their reaction mixturesand, if necessary, purified using conventional techniques as known tothose skilled in the art. Thus, processes for preparation of compoundsof the invention as described herein may include, as a final step,isolation and optionally purification of the compound of the invention(e.g. isolation and optionally purification of the compound of formulaI).

It will be appreciated by those skilled in the art that, in theprocesses described above and hereinafter, the functional groups ofintermediate compounds may need to be protected by protecting groups.The protection and deprotection of functional groups may take placebefore or after a reaction in the above-mentioned schemes.

Protecting groups may be applied and removed in accordance withtechniques that are well known to those skilled in the art and asdescribed hereinafter. For example, protected compounds/intermediatesdescribed herein may be converted chemically to unprotected compoundsusing standard deprotection techniques. The type of chemistry involvedwill dictate the need, and type, of protecting groups as well as thesequence for accomplishing the synthesis. The use of protecting groupsis fully described in “Protective Groups in Organic Synthesis”, 3rdedition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1999).

Compounds of the invention may have the advantage that they may be moreefficacious than, be less toxic than, be longer acting than, be morepotent than, produce fewer side effects than, be more easily absorbedthan, and/or have a better pharmacokinetic profile (e.g. higher oralbioavailability and/or lower clearance) than, and/or have other usefulpharmacological, physical, or chemical properties over, compounds knownin the prior art, whether for use in the above-stated indications orotherwise. In particular, compounds of the invention may have theadvantage that they are more efficacious and/or exhibit advantageousproperties in vivo.

Without wishing to be bound by theory, it is thought that inhibition ofthioredoxin reductase is obtained by the utilization of strongelectrophilicity of small molecule inhibitors in combination with apronounced inherent nucleophilicity of NADPH-reduced, but not oxidized,thioredoxin reductase, resulting in selective and potent inhibition ofsaid enzyme without major targeting of other cellular pathways orenzymes.

Moreover, it is thought that normal non-cancerous cells may survivewithout a functional cytosolic thioredoxin reductase enzyme because ofmaintained function of the glutathione system, while cancer cells cannotsurvive upon specific inhibition of cytosolic thioredoxin reductase.

Without wishing to be bound by theory, it is believed that compounds ofthe invention may be active per se and/or may act as prodrugs of activecompounds in the form of the corresponding sulfonyl compounds (i.e.compounds of the invention but wherein L represents —S(O)₂—), such asmay be described in WO 2017/027359 (the contents of which, including theexamples provided therein, is incorporated herein by reference).

EXAMPLES

The invention is illustrated by way of the following examples, in whichthe following abbreviations may be employed.

-   aq aqueous-   BSA bovine serum albumin-   conc concentrated-   DMA N,N′-dimethylacetamide-   DMF N,N′-dimethylformamide-   DMSO dimethyl sulfoxide-   DTNB 5,5′-dithio-bis-(2-nitrobenzoic acid)-   EDTA ethylenediaminetetraacetic acid-   GSSG glutathione disulfide-   HPLC high performance liquid chromatography-   HRMS high resolution mass spectrometry-   mCPBA meta-chloroperbenzoic acid-   NADPH nicotinamide adenine dinucleotide phosphate-   NMR nuclear magnetic resonance-   PBS phosphate buffered saline-   rt room temperature

Starting materials and chemical reagents specified in the synthesesdescribed below are commercially available from a number of suppliers,such as Sigma Aldrich.

In the event that there is a discrepancy between nomenclature and thestructure of compounds as depicted graphically, it is the latter thatpresides (unless contradicted by any experimental details that may begiven and/or unless it is clear from the context). Final compounds arenamed using ChemBioDraw Ultra 14.

Example 1: 2-((4-Chlorophenyl)sulfinyl)-6-methoxy-3-nitropyridine

(a) 2-((4-chlorophenyl)thio)-6-methoxy-3-nitropyridine

A mixture of 2-chloro-6-methoxy-3-nitropyridine (1.00 g, 5.32 mmol),4-chlorothiophenol (0.84 g, 5.87 mmol), K₂CO₃ (0.22 g, 1.62 mmol) andDMF (20 mL) was stirred at rt for 4 h. The mixture was poured ontocrushed ice, allowed to reach rt and filtered. The solids were washedwith H₂O and dried to get the sub-title compound (0.90 g, 57%).

¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J=8.9 Hz, 1H), 7.49 (d, J=8.3 Hz,2H), 7.40 (d, J=8.3 Hz, 2H), 6.49 (d, J=8.9 Hz, 1H), 3.41 (s, 3H).

(b) 2-((4-Chlorophenyl)sulfinyl)-6-methoxy-3-nitropyridine

mCPBA (0.87 g, 5.07 mmol) was added in portions to a stirred mixture of6-chloro-2-((4-chlorophenyl)thio)-3-nitropyridine (1.00 g, 3.37 mmol)and CH₂Cl₂ (10 mL) at rt. The mixture was stirred at rt overnight,diluted with CH₂Cl₂, washed twice with Na₂S₂O₃ (aq, sat) and then withbrine. The phases were separated and the organic layer was dried overNa₂SO₄ and concentrated. Purification by chromatography gave the titlecompound (0.65 g, 62%).

¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J=8.9 Hz, 1H), 7.90 (dd, J=6.9/1.6Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.9 Hz, 1H), 4.25 (s, 3H).

MS: m/z (M+H)+=(Calculated for C₁₂H₉ClN₂O₃S+H: 313.01) found 313.0.

BIOLOGICAL EXAMPLES Biological Example 1: Inhibition of RecombinantTrxR1 and GR

Small molecule inhibition of recombinant thioredoxin reductase 1 (TrxR1)and gluthathione reductase (GR) was examined in 96-well plate format. 30nM TrxR1 was incubated in the presence of 250 μM NADPH, 0.1 mg/ml BSA,and various concentrations of compound (1% DMSO final) in 50 mM Tris (pH7.5) and 2 mM EDTA buffer for 15 minutes. Following the incubationperiod, 2 mM DTNB was added to each well and the change in O.D. at 412nm was followed. Percent activity was determined using DMSO vehicle andno TrxR1 (blank) controls. 2 nM GR was incubated in the presence of 250μM NADPH, 0.1 mg/ml BSA, and various concentrations of compounds (1%DMSO final) in 50 mM Tris (pH 7.5) and 2 mM EDTA buffer for 15 minutes.Following the incubation period, 1 mM GSSG was added to each well andthe change in O.D. at 340 nm was followed. Percent activity wasdetermined using DMSO vehicle and no GR (blank) controls.

Using the assays described in Biological Example 1, the following IC₅₀values were obtained. The results obtained are provided in Table 1below.

Example TrxR inhibition (nM) GR inhibition (μM) 1 3.16 41.32

Biological Example 2: Breast Cancer Cell Viability Assay

MDA-MB-231 cells were plated 2000 cells/well in 96-well black opticalplates in the presence of 10% FBS media containing 25 nM selenite. Thefollowing day cells were treated with various concentrations ofcompounds (0.1% DMSO final) and incubated for 72 hrs. After theincubation Alamar Blue reagent was added to each well and incubated foradditional 3 hrs. Fluorescence was read ex:530 nm/em:590 nm, and percentof viability was determined using DMSO vehicle and no cell (blank)controls.

Using the assays described in Biological Example 2, the following IC₅₀values were obtained. The results obtained are provided in Table 2below.

MDA-MB-231 Cell Example # viability IC50 (μM) 1 2.99

Biological Example 3: Cancer Cell Viability Assay

Breast cancer and glioblastoma cell lines were plated 4000 cells/well in96-well plates in the presence of 10% FBS media. The following day cellswere treated with various concentrations of the compound of Example 1(0.1% DMSO final) and incubated for 72 hrs. After the incubation An MTTassay was performed to access cell viability. Percent of viability wasdetermined using DMSO vehicle and no cell (blank) controls.

Using the assays described in Biological Example 3, the following IC₅₀values were obtained. The results obtained are provided in Table 3below.

MDA-MB- MDA-MB- U-87 MG 231 IC50 468 IC50 Example # IC50 (μM) (μM) (μM)1 6.76 5.26 3.86

1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein: L represents—S(O)—; n represents 0 to 5; R¹, R² and R³ each independently representH, halo, R^(a1), —CN, -A^(a1)-C(Q^(a1))R^(b1),-A^(b1)-C(Q^(b1))N(R^(c1))R^(d1), -A^(e1)-C(Q^(e1))OR^(e1),-A^(d1)-S(O)_(p)R^(f1), -A^(e1)-S(O)_(p)N(R_(g1))R^(h1),-A^(f1)-S(O)_(p)OR^(i1), —N₃, —N(R^(j1))R^(k1), —N(H)CN, —NO₂, —ONO₂,—OR^(l1) or —SR^(m1); each A^(a1) to A^(f1) independently represents asingle bond, —N(R^(p1))— or —O—; each Q^(a1) to Q^(c1) independentlyrepresents ═O, ═S, ═NR^(n1) or ═N(OR^(o1)); each R^(a1) and R^(f1)independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl eachoptionally substituted by one or more groups independently selected fromG^(1a), heterocyclyl optionally substituted by one or more groupsindependently selected from G^(1b), aryl optionally substituted by oneor more groups independently selected from G^(1c), or heteroaryloptionally substituted by one or more groups independently selected fromG^(1d); each R^(b1), R^(c1), R^(d1), R^(e1), R^(g1), R^(h1), R^(i1),R^(j1), R^(k1), R^(l1), R^(m1), R^(n1), R^(o1) and R^(p1) independentlyrepresents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionallysubstituted by one or more groups independently selected from G^(1a),heterocyclyl optionally substituted by one or more groups independentlyselected from G^(1b), aryl optionally substituted by one or more groupsindependently selected from G^(1c), or heteroaryl optionally substitutedby one or more groups independently selected from G^(1d); or any ofR^(c1) and R^(d1), R^(g1) and R^(h1) and/or R^(j1) and R^(k1) are linkedtogether to form, together with the nitrogen atom to which they areattached, a 3- to 6-membered ring, which ring optionally contains onefurther heteroatom and which ring optionally is substituted by one ormore groups independently selected from halo, C₁₋₃ alkyl, C₂₋₃ alkenylor C₂₋₃ alkynyl each optionally substituted by one or more halo, and =0;each R⁴ independently represents halo, R^(a2), —CN,-A^(a2)-C(Q^(a2))R^(b2), -A^(b2)-C(Q^(b2))N(R^(c2))R^(d2),-A^(c2)-C(Q^(c2))OR^(e2), -A^(d2)-S(O)_(q)R^(f2),-A^(e2)-S(O)_(q)N(R^(g2))R^(h2), -A^(f2)-S(O)_(q)OR^(i2), —N₃,—N(R²)R^(k2), —N(H)CN, —NO₂, —ONO₂, —OR^(l2) or —SR^(m2); each Q^(a2) toQ^(c2) independently represents ═O, ═S, ═NR^(n2) or ═N(OR^(o2)); eachA^(a2) to A^(f2) independently represents a single bond, —N(R^(p2))— or—O—; each R^(a2) and R^(f2) independently represents C₁₋₆ alkyl, C₂₋₆alkenyl or C₂₋₆ alkynyl each optionally substituted by one or moregroups independently selected from G²a, heterocyclyl optionallysubstituted by one or more groups independently selected from G^(2b),aryl optionally substituted by one or more groups independently selectedfrom G²c, or heteroaryl optionally substituted by one or more groupsindependently selected from G^(2d); each R^(b2), R^(c2), R^(d2), R^(e2),R^(g2), R^(h2), R^(i2), R^(j2), R^(k2), R^(l2), R^(m2), R^(n2), R^(o2)and R^(p2) independently represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl each optionally substituted by one or more groups independentlyselected from G^(2a), heterocyclyl optionally substituted by one or moregroups independently selected from G^(2b), aryl optionally substitutedby one or more groups independently selected from G^(2c), or heteroaryloptionally substituted by one or more groups independently selected fromG^(2d); or any two R^(c2) and R^(d2), R^(g2) and R^(h2) and/or R^(j2)and R^(k2) are linked together to form, along with the nitrogen atom towhich they are attached, a 3- to 6-membered ring, which ring optionallycontains one further heteroatom and which ring optionally is substitutedby one or more groups independently selected from halogen, C₁₋₃ alkyl,C₂₋₃ alkenyl or C₂₋₃ alkynyl each optionally substituted by one or morehalogens, and =0; each G^(1a), G^(1b), G^(1c), G^(1d), G^(2a), G^(2b),G^(2c) and G^(2d) independently represents halo, —CN, —N(R^(a3))R^(b3),—OR^(c3), —SR^(d3) or ═O; each R^(a3), R^(b3), R^(c3) and R^(d3)independently represents H, or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyleach optionally substituted by one or more fluoro; or R^(a3) and R^(b3)are linked together to form, along with the nitrogen atom to which theyare attached, a 3- to 6-membered ring, which ring optionally containsone further heteroatom and which ring optionally is substituted by oneor more groups independently selected from fluoro, C₁₋₃ alkyl optionallysubstituted by one or more fluoro, and ═O; and each p and qindependently represents 1 or 2, but with the proviso that the compoundof formula I does not represent: 3-nitro-2-(phenylsulfinyl)pyridine,3-nitro-2-(p-tolylsulfinyl)pyridine,2-((4-bromophenyl)sulfinyl)-3-nitropyridine,2-((3-chlorophenyl)sulfinyl)-3-nitropyridine, or3-nitro-2-((3-(trifluoromethyl)phenyl)-sulfinyl)pyridine.
 2. A compoundas claimed in claim 1, wherein each R⁴ independently represents halo,—N(R^(j2))R^(k2), —OR^(l2), or R^(a2).
 3. A compound as claimed in claim1, wherein each R¹, R² and R³ each independently represents H, halo,R^(a1), —N(R^(j1))R^(k1), —OR^(l1) or —SR^(m1).
 4. A compound as claimedin claim 1, wherein each R^(a2) independently represents C₁₋₆ alkyl(e.g. methyl) optionally substituted by one or more fluoro, and eachR^(j2), R^(k2) and R^(l2) independently represents H or C₁₋₆ alkyloptionally substituted by one or more fluoro.
 5. A compound as claimedin claim 1, wherein n represents 0 or
 1. 6. A compound as claimed inclaim 1, wherein n represents at least 1 and one R⁴ group is present inthe 4-position.
 7. A compound as claimed in claim 1, wherein each R⁴independently represents halo.
 8. A compound as claimed in claim 1,wherein R¹, R² and R³ each independently represent H, halo, R^(a1),—N(R^(j1))R^(k1) or —OR^(l1).
 9. A compound as claimed in claim 1,wherein each R^(a1), R^(j1), R^(k1), R^(l1) and R^(m1) independentlyrepresent C₁₋₆ alkyl optionally substituted by one or more fluoro.
 10. Acompound as claimed in claim 1, wherein R¹, R² and R³ each independentlyrepresent H, halo, —N(R^(j1))R^(k1) or —OR^(l1).
 11. A compound asclaimed in claim 1 to 10, wherein: R² and R³ represent H; and/or R¹represents H, chloro, —N(C₁₋₆ alkyl)C₁₋₆ alkyl or —OC₁₋₆ alkyl, whereinthe latter two groups are optionally substituted by one or more fluoro.12. A compound as claimed in claim 1, wherein: R² and R³ represent H;and/or R¹ represents —OCH₃. 13-15. (canceled)
 16. A method of treatingcancer comprising administering to a patient in need thereof atherapeutically effective amount of a compound as defined in claim 1 butwithout the proviso.
 17. The method of claim 16, wherein the cancer isselected from the group consisting of: soft tissue cancers, such assarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lungcancers, such as bronchogenic carcinoma, alveolar or bronchiolarcarcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoushamartoma, mesothelioma; gastrointestinal cancers: such as esophagealcancers, stomach cancers, pancreatic cancers, small bowel cancers, largebowel cancers; genitourinary tract cancers, such as cancer of thekidney, bladder and urethra, prostate, testis; liver cancers, such ashepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma,hepatocellular adenoma, hemangioma; bone cancers, such as osteogenicsarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma,Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giantcell tumor chordoma, osteochronfroma, benign chondroma, chondroblastoma,chondromyxofibroma, osteoid osteoma and giant cell tumors; cancers ofthe head and/or nervous system, such as cancer of the skull, meninges,brain, spinal cord; gynecological cancers, such as cancers of theuterus, cervix, ovaries, cancers of the vulva, vagina, fallopian tubes;haematologic cancers, such as cancers of the blood and bone marrow,Hodgkin's disease, non-Hodgkin's lymphoma; skin cancers, such asmalignant melanoma, basal cell carcinoma, squamous cell carcinoma,Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids; neurofibromatosis and adrenal glands; andneuroblastomas.
 18. The method of claim 17, wherein the cancer is asolid tumor cancer.
 19. A pharmaceutical composition comprising acompound as defined in claim 1 but without the proviso, and optionallyone or more pharmaceutically acceptable adjuvant, diluent and/orcarrier.
 20. A combination product comprising: (A) a compound as definedin claim 1 but without the proviso; and (B) one or more othertherapeutic agent that is useful in the treatment of cancer, whereineach of components (A) and (B) is formulated in admixture, optionallywith one or more a pharmaceutically-acceptable adjuvant, diluent orcarrier.
 21. A kit-of-parts comprising: (a) a pharmaceutical formulationas defined in claim 19 but without the proviso; and (b) one or moreother therapeutic agent that is useful in the treatment of cancer,optionally in admixture with one or more pharmaceutically-acceptableadjuvant, diluent or carrier, which components (a) and (b) are eachprovided in a form that is suitable for administration in conjunctionwith the other.
 22. A process for the preparation of a compound asdefined in claim 1, which process comprises: reaction of a compound offormula II

wherein R¹ to R⁴ and n are as defined in claim 1, with a suitableoxidising agent in the presence of a suitable solvent.